Multilateral-physiological and functional evidences of the heme oxygenase-1 (HO-1) enzyme : learning from the first case with human HO-1deficiency

第一次描述的情况下，人类血红素氧合酶-1（HO-1）缺乏症。该患者为6岁男孩，与HO-1基因敲除小鼠相似，表现出严重的生长迟缓、贫血、肾和肝组织铁沉积以及易受应激相关损伤伴高热。(1)基因组分析显示，该男孩完全缺乏HO-1，具有该基因的母系等位基因的外显子2的缺失和父系等位基因的外显子3的两个碱基对的缺失。进一步的分析显示，在这种情况下，基因组外显子缺失（1，730 bp）介导的EST-Alu重组的结构证据。(2)该男孩表现出单核细胞形态异常，其表面分子包括CD 11b、CD 14、CD 16和CD 36显著减少，导致单核细胞吞噬功能明显受损。我们研究了单核细胞HO-1生产在两个体内模型系统的重要性。在急性发热性疾病中，单核细胞被激活， ...更多信息 f HO-1生产。此外，我们还检测了儿童肺动脉高压时肺泡巨噬细胞产生HO-1的情况，显示HO-1水平与肺动脉高压程度有良好的相关性。(3)本例连续三次肾活检标本均可见肾小球毛细血管壁厚度的系膜改变。肾小管间质损伤伴肾小管扩张和/或萎缩、间质纤维化和炎性细胞浸润进行性进展。电子显微镜检查显示广泛的内皮脱离和无法识别的材料的内皮下沉积物。此外，我们比较了HO-1的表达模式和应激诱导的细胞毒性的原代培养的人肾小球系膜细胞（hMCs）和近端肾小管上皮细胞（hTECs）在体外的反应。hTECs被证明是更容易受到氧化应激和显着更依赖于HO-1的表达比hMCs。(4)我们转染HO-1基因使HO-1表达水平最低的ECV 304细胞死亡。HO-1高表达的细胞比HO-1低表达的细胞表现出更多的H2 O2引起的细胞死亡，表明HO-1高表达并不总是预防应激诱导损伤的良好预后因素。少

The first-described case of human heme oxygenase-1 (HO-1) deficiency is presented. The patient, a 6-year-old boy, similar to HO-1 knockout mice, exhibited severe growth retardation, anemia, iron deposition in renal and hepatic tissue, and vulnerability to stress-related injury with high fever.(1) The genomic analysis revealed that the boy completely lacked HO-1, having a deletion of exon 2 of the maternal allele and a two-base-pair deletion in exon 3 of the paternal allele of the gene. Further analysis revealed structural evidence of genomic exon-deletion (l,730bp) mediated by Alu-Alu recombination in this case.(2) The boy exhibited morphological abnormality of monocytes and significant reduction of their surface molecules including CD11b, CD 14, CD16 and CD36, resulting in a markedly impaired phagocytosis of monocytes. We investigated the importance of monocyte HO-1 production in two in vivo model systems. In acute febrile illnesses monocytes are activated with simultaneous increase o … More f HO-1 production. In addition, we also examined HO-1 production by alveolar macrophages in childhood pulmonary hypertension, showing well correlation of the level of HO-1 with the degree of pulmonary hypertension.(3) Renal mesangial change in glomerular capillary-wall thickness was shown in the three consecutive biopsy specimens in this case. Tubulointerstitial injury, with tubular dilatation and/or atrophy, interstitial fibrosis, and inflammatory cell infiltration advanced progressively. Electron microscopic examination showed widespread endothelial detachment and subendothelial deposits of an unidentifiable material. Furthermore, we compared the patterns of HO-1 expression and the responses to stress-induced cytotoxicity by primary cultured human mesangial cells (hMCs) and proximal tubular epithelial cells (hTECs) in vitro. The hTECs were shown to be more susceptible to oxidative stress and significantly more dependent on HO-1 expression than the hMCs.(4) We transfected HO-1 gene to die ECV304 cells with a minimal level of HO-1 expression. The high HO-1-expressed cells showed more increase of cell death by H2O2 than die low HO-1-expressed one, indicating that the high expression of HO-1 was not always a good prognostic factor for prevention of stress-induced injuries.From these data based on the first human case of HO-1 deficiency, multilateral physiological functions of die HO-1 enzyme were newly evidenced. Less